Tetrandrine, or TTD, with the chemical formula of 6,6′,7,12-tetramethoxy-2,2′dimethylberbamine, is a bisbenzylisoquinoline alkaloid extracted from the root block of the Chinese herbal fangji. Tetrandrine has the effect of inhibiting the central nerves, as well as anti-inflammatory, analgesic and antipyretic effects. It directly expands peripheral blood vessels, leading to a prominent and persistent antihypertensive effect, and thus can find use in rheumatic pain, arthritis, neuralgia, muscle pain and various types of hypertension. Tetrandrine has negative inotropic effect, negative chronotropic effect and negative dromotropic effect on heart. Further, tetrandrine reduces myocardial consumption of oxygen, prolongs the myocardial refractory period and atrioventricular conduction, increases myocardial blood flow, reduces the total peripheral vascular resistance and brings down the blood pressure, during which the baroreflex-heart rate is not increasing. Due to the reduction of the afterload, the cardiac output may increase. These effects are all associated with the calcium antagonism thereof.
Therefore, tetrandrine and its derivatives and analogs are extensively studied around the world (Ji, Yubin et al., Pharmacology of the Effective Components of Traditional Chinese Medicine and Their Applications. Harbin: Heilongjiang Science and Technology Press, 1995; Su, J. Y. Naunyn-Schmiedeberg's Arch Pharmacol. 1993. 347:445-451; Wei, N.; Sun, H.; Wang, F. P. Cancer Chenother Pharmacol. 2011, 67:1017-1025; Rahman, A. U. Chem Pharm Bull, 2004, 52(7): 802; Wang, Jiwu et al., Handbook of the Effective Components of Plant Drugs. Beijing: People's Medical Publishing House, 1986; Knox, V. D. Use of tetrandrine and its derivatives to treat malaria. [P]. U.S. Pat. No. 5,025,020. 1991; Virginio, C.; Graziani, F.; Terstappen, G. C. Neuroscience Letters. 2005. 381:299-304; Karen, O. L.; Carolina, G. A.; Alexey, v. E.; Anatoly, K. Y. Org. Biomol. Chem. 2004, 2:1712-1718; Lin, Mubin et al., Chemical Research on Tetrandrine-N-oxides, Acta Chimica Sinica, 1984, 42(2):199-203; Tsutsumi, T.; Kobayashi, S.; Liu, Y. Y.; Kontani, H. Biol. Pharm. Bull. 26(3):313-317).
Tetrandrine and some derivatives or analogs thereof are as follows.

Tetrandrine exhibits inhibition on the proliferation of cervical cancer HeLa cells. The studies use the MTT method to detect inhibition on the proliferation of the cervical cancer HeLa cell lines by tetrandrine in various concentrations and at different time. The cell apoptosis is detected by a flow cytometer and a confocal laser scanning microscopy. As is shown by the experiments, tetrandrine exhibits inhibition on proliferation of the cervical cancer HeLa cells, which has dependency on time and concentration. (Zhu Kexiu et al., Qualitative and quantitative studies on tetrandrine-induced apoptosis of cervical cancer cells, Journal of Xi'an Jiaotong University (Medical Sciences Edition), 2010, 31 (1), 102).
Tetrandrine can inhibit the proliferation of hepatoma cells. After tetrandrine acting on the hepatoma cells, reactive oxygen species (ROS) are generated within 2 hours, and the production of ROS increases significantly with the increase of dose. It is suggested that tetrandrine may generate reactive oxygen species by interfering with the mitochondrial function, which causes the cell lipid peroxidation, damages the DNA molecules or regulates related genes of apoptosis, thereby inhibiting the proliferation of hepatoma cells. (Jing Xubin et al., Experimental studies on the tetrandrine-induced oxidative damage of hepatoma cells, Journal of Clinical Hepatology, 2002, 18 (6), 366).
It is also reported that in vitro tetrandrine has obvious inhibitory effect on the growth of human neuroblastoma cell line TGW. Studies show that such inhibition gradually increases with the increase of dose, and such inhibition also increases apparently with prolonged inhibition time, showing a good dose-time correlation (Li Weisong et al., Journal of Clinical Pediatrics, Experimental studies on tetrandrine-induced apoptosis of neuroblastoma cell line TDW, 2006, 24 (6), 512).
In addition to the above effects of interferencing tumor cells, inhibiting their proliferation, inducing cell apoptosis and tumor growth, tetrandrine can also regulate the drug resistance of P-glycoprotein-mediated multidrug resistant cells and conduct the down regulation of the expression of the drug-resistant gene mdr1mRNA.
Some reports have proved by in vitro experiments that, after the application of tetrandrine in drug-resistant lung cancer, the drug-resistance index is reduced from 5.43 (while adriamycin is used) to 1.89, indicating that tetrandrine can reverse the drug resistance of drug-resistant lung cancer cell GLC-82/ADR to adriamycin. In addition, research is conducted on the reversal effect of tetrandrine on the human breast cancer multidrug resistant lines MCF-7/ADR, which has found out that 2.5 μmol/L tetrandrine can increase the adriamycin cytotoxicity on drug-resistant tumors by 20.4 times, indicating that tetrandrine has enormous potential in reversing the tumor ADR (Xu Meng et al., Experimental studies on the reversal of lung cancer chemotherapy resistance and resistance to apoptosis by tetrandrine, Practical Journal of cancer, 2003, 18(4): 347; Fu, L. W, et al. The multidrug resistance of tumour cells was reversed by tetrandrine in vitro and in xenografts derived from human breast adenocarcinoma MCF-7/adr cells. European Journal of Cancer, 2002, 38(3):418).
In addition, clinical experiments also substantiate that tetrandrine can promote the irradiated cancer cells to enter M phase from G2 phase, which shortens the time for the damage repair of radiotherapy cells, thereby achieving the purpose of radiosensitization.
Based on the experimental studies on tetrandrine increasing the radiosensitivity of breast cancer cells, some reports draw the conclusion that the cell cycle arrest induced after the irradiation is closely related to the p53 gene function. After cells receiving gamma irradiation, the Cyclin B1 and Cdc2 protein expression levels thereof are significantly lowered, and the mitotic index also decreases significantly, indicating that tetrandrine serves for removing G2-phase arrest, so as to significantly enhance the killing effect of gamma radiation on human breast cancer cells. In addition, some studies have also found that tetrandrine has radiosensitizing effect on stereo experiment of human esophageal cancer TE1 cells. Low concentrations of tetrandrine are chosen in some experiments to investigate the radiosensitizing effect, and it was found that the TE1 cell survival fraction exponentially declines with the increase of radiation dose, and that the maximum radiosensitization of 1.62 is reached at the drug concentration of 0.5 μg/mL, indicating that tetrandrine has certain radiosensitizing effect on esophageal cancer cells cultured in vitro, and the underlying mechanism may be that the G2+M phase cell arrest is removed by the increased expression of cyclin B1 (Tian Qingzhong et al., Study of potentiation of radiosensitivity by tetrandrine and its mechanism, Journal of Southeast University, 2005, 24 (4), 233; Yu Jingping et al., Radiosensitizing effect of tetrandrine in human esophageal carcinoma cells: A preliminary in vitro study, Chinese Journal of Radiation Oncology, 2010, 19 (6), 568).
It is apparent that tetrandrine medicaments of high activity are still needed in the market. Up to now, no reports have yet been seen on the synthesis and applications of tetrandrine derivatives modified and substituted on 5-carbon.